Drug Carrier with Chelating Complex Micelles and the Application thereof

ABSTRACT

This invention provides Chelating Complex Micelles as a drug carrier. The Chelating Complex Micelles can load drugs without changing their structure, and therefore extend the half-life of drugs in the human body. The chelating complex micelles contain a metal ion core, at least one polymer, and at least one drug molecule. The metal ion is considered as a Lewis acid while polymer chain and drug molecules are referred to as Lewis bases. The drug molecule is linked to the polymer via forming coordinate bonds with metal ion, and then self-assembled to form chelating complex micelles as a drug carrier.

FIELD OF THE INVENTION

The present invention is a drug carrier, in particular, a chelatingcomplex micelle drug carrier, and its formation and formulation.

BACKGROUND OF THE INVENTION

Adverse effects, occurred in cancer patients receiving radiation therapyand chemotherapy, are well known. The toxicity of anticancer therapy hasalways been a major concern of patients because such therapy causesserious adverse effects. For patients who cannot complete the intendedcourse of treatment, the therapy not only fails to achieve the desiredand predicted outcome but the medical resources are also wasted. Becauseof its relatively non-selective action on both normal and cancer cells,radiation therapy and chemotherapy not only eliminate cancer cells butmay also kill normal cells. Common adverse effects for patientsreceiving these treatments include oral ulcers, loss of appetite,diarrhea, hair loss, and a decrease of white blood cells and platelets,which can lead to other fatal complications. Adverse effects often limitthe therapeutic dosages administered, and hence the therapeuticefficacy; part of the adverse effects can be reduced by changing drugdelivery, such as dividing the doses or increasing the administrationduration or local administration. Examples of the latter includeintraperitoneal or intra-arterial chemotherapy, which limits thesystemic adverse effects by confining high concentrations of drugs tothe lesion sites; or administering antagonists (or antidotes) after thedrugs have exerted their therapeutic effects, which may reduce the toxiceffects of anticancer drugs on normal cells. However, the aboveapproaches are not selective, and there is only a marginal decrease inthe toxicity to normal cells; moreover, the therapeutic efficacy oncancer cells is also compromised. The alternative approach is to treatthe adverse effects immediately after drug administration to minimizethe harmful effects, such as administering white blood cell growthfactors and potent antiemetic agents; however, this approach onlypartially reduces the existing adverse effects, and lacking preventiveeffects. It is impossible to have a drug exhibiting only therapeuticeffect and no adverse effects. Furthermore, once the tumor is formed,relentless replication and growth of cancer cells will metastasize todistant organs via blood and lymphatic vessels, which may ultimatelyproduce drug resistance cancer cells leading to treatment failure.Anticancer and radiation therapy are no longer effective in controllingtumor growth and spread. Accordingly, the focal point to consider inradiotherapy and chemotherapy is to attack cancer cells whileconcomitantly protect normal cells to reach the goal of radiotherapy andchemotherapy. Since the action mechanism of chemotherapy and radiationtherapy is partially due to free radical damage, a rational selectiveutilization of substances possessing both antioxidant and free radicalproperty can reduce the damage to normal cells under such treatment.

Amifostine (Ethyol; WR-2721) is a thiophosphate cytoprotective agentagainst radiation damage. It is a precursor of phosphorylatedaminothiol, which is converted to an active free thiol metabolite,WR-1065, by alkaline phosphatase in the cells, body fluids and blood.WR-1065 can protect the cells from radiation and chemical damage,thereby protecting cancer patients from serious adverse effects causedby radiotherapy and chemotherapy. The alkaline phosphatase level incancer cells is much lower than that of normal cell, and the conditionof blood flow and the acidic environment surrounding cancer cells arealso unfavorable for alkaline phosphatase. The tissue protective effectcan combine with the active alkylating agents and platinum analogs toform thioether conjugates, which can prevent alkylating agents andplatinum analogs from combining with the normal tissue DNA or RNA. Inaddition, WR-1065 can partially reverse the preformed endogenousDNA-platinum adduct assisting the removal of DNA-platinum, and allowingnormal DNA to function. WR-1065 can also provide H⁺ ion for the repairof DNA damage. WR-1065 is also a potent ROS (reactive oxygen species)scavenger. It can eliminate the ROS generated by radiation therapy andcertain chemotherapeutic drugs to prevent cell damage. In in vitro,WR-1065 can effectively eliminate hydroxyl radical (OH)-relatedspin-trap signal, superoxide anion and doxorubicin-derived superoxideanion. The scavenging effect of WR-1065 on ROS can be used to preventbleomycin induced pulmonary inflammation and fibrosis.

Amifostine can reduce the toxic effects and protect normal tissue fromcancer chemotherapy; it can increase the effective dosage and responserate of chemotherapy and radiation therapy. In addition, amifostine whencombined with other growth factors or cytokines can exert synergisticprotection on hematopoietic stem cells. The cytoprotective effect ofamifostine appears 5-10 minutes after injection with short bloodhalf-life (βt_(1/2)=8.8 min), rapid plasma clearance with approximately90% cleared within 6 minutes. Amifostine is rapidly distributed tovarious tissues, dephosphorylated, and reaches a steady state in about10 minutes. In contrast, the distribution of amifostine to tumor tissueis much less and also slowly dephosphorylated to active metabolite.Following injection, the concentration of amifostine in normal cells,including kidney, lung, liver, skin, bone marrow, intestine and spleen,is 10 times that of cancer cells. Amifostine is much less distributed tobrain tissue, skeletal muscle and tumor cells. Amifostine exertsselective protective effect on normal cells, but must be administered 15to 30 minutes prior to chemotherapy or radiation therapy. However,routine treatment requires several hours, therefore, how to extend thehalf-life of amifostine in the human body becomes the major developmenttarget of the drug industry.

In addition to aforementioned amifostine, the half-life of usual dosageforms of drugs in the body is usually very short; followingadministration or injection into the body, these drugs may distribute tovarious tissues. In order to maintain a long period of action andeffective drug distribution, higher dosages or multiple dosing beyondthe effective blood concentration are necessary. However, administrationof high dosages is toxic to body tissues and causes unnecessary adverseeffects. To circumvent the shortcomings of conventional repeated dosingand to avoid overdose and waste of the drug, the DDS (drug deliverysystem) concept has been formulated to increase the efficacy of drugsand reduce the number of dosages. A commercially available carrier suchas liposomes (or liposome capsule) is a spherical carrier which isformed by a single or multiple layers of phosphatidylcholine (PC). Thestructure constraints of these liposomes only permit it to carryhydrophilic drugs (in the inner core). These carriers are particularlyprone to accumulating in the liver, very sensitive to temperaturechange, difficult to store, and not easy to transport in dry powder form(see C. Chen, D. Han, et al. (2010). “An overview of liposomelyophilization and its future potential.” Journal of Controlled Release142: 299-311).

Polymeric micelles demonstrate excellent potential as a drug carrier.The advantages include improved drug efficacy, improved protection andstabilization of drugs, reduced cytotoxicity, and better delivery to theintended targets. Furthermore, nano-scaled micelles have extendedcirculation time; far less effect or degradation from macrophage(mononuclear phagocyte system, MPS) and endoplasmic reticulum (reticularepithelial system, RES) system. Currently, it is the focus of drugdelivery system (DDS). Polymeric micelles are commonly composed ofamphiphilic block copolymers. In the aqueous solution, the polymerchains self-assemble to form the micelles with a core-shell structure,thus providing an excellent reservoir (inside the core) for hydrophobicdrugs (such as: indomethacin, doxorubicin, amphotericin B). Usingpolymeric micelles to deliver drugs may also improve their stability andefficacy. Drugs can be loaded by polymeric micelles through physicalencapsulation, chemical bonding or electrostatic interactions. Thedriving force of physical encapsulation is primarily the interactionsbetween the hydrophobic segment of the polymer and the hydrophobic partof the drug. The chemical bonding uses covalent bond to link drugmolecule to polymer, such as amide bond, which is very stable, lesssusceptible to enzyme degradation or hydrolysis. A spacer that can bebroken down under specific condition must be introduced between the drugmolecule and the polymer chain to facilitate the release of the drugmolecule. The physical forces only limit to encapsulate hydrophobicdrugs; drugs loaded through chemical bonding requires complicatedsynthetic steps, thus resulting in lower loading rate.

In addition to physical encapsulation and covalent bonding mentioned inthe previous section, electrostatic interaction has also been attemptedin polymeric micelles. For this, the polymers are designed so that oneend segment is undissociated while the other end is ionizable. In theappropriate medium, the ionizable segments interact with oppositelycharged drugs, thus forming polyion complex micelles (PIC micelles) withcore-shell structure. However, the use of electrostatic force to carrydrugs also has limitations. The drugs with low molecular weight or highwater-solubility are easily displaced by the ions in solution. Anotherapproach is direct bonding of drugs to the carriers, especiallymetal-containing drugs such as cisplatin, carboplatin, or oxaliplatin.However, these metal-containing drugs are taken as Lewis acids, and itsfunctional groups will be replaced when bound to carriers. Thealteration of structure is considered as a new drug, which necessitatesreevaluating the safety and efficacy. This may lead to a significantincrease in cost. Accordingly, developing a new drug delivery carrier isthe major target that the industry desperately needs.

SUMMARY OF THE INVENTION

From the background information presented above and to accommodate thespecial needs of the industry, the present invention provides achelate-type drug carrier with coordination bonds to address the unmetobjectives encountered in the conventional technology.

The aim of the present invention is to provide a drug carrier containinga metal ion core. This carrier comprises a metal (including transitionmetals) at the center (i.e., metal core), which interacts with thepolymer (including block copolymers) possessing chelating ligands toform the coordinate bonds. Drugs that can donate a lone pair ofelectrons (including drugs possessing functional groups, such ascarboxylic acids, alcohols, ketones, furans, amines, anilines, pyrroles,thiols, esters, amides, imines, pyridines, pyrimidines, imidazoles,pyrazols, sulfonamides, phosphonic acids, etc.) can also bind to metalcenter through coordinate bonds, which then form a complex, or chelatingcomplex micelles (CCM) with the polymer containing chelating ligands.The coordinate bond (also known as dipolar bond) is a special kind ofcovalent bond in which the two electrons derive from the same atom. Theformation of coordinate bond requires two conditions: first, the metalion must have an incomplete octet of electrons; and second, the liganddonates a lone pair of electrons. Typically, a coordinate bond is formedwhen a Lewis base donates a pair of electrons to a Lewis acid. Inreality the atoms carry fractional charges; the more electronegativeatom of the two involved in the bond will carry a fractional negativecharge.

The preparation of present invention, chelating complex micelles (CCM),is much easier than the physical encapsulation and chemical bonding ofdrugs. Physical encapsulation that requires large quantities of organicsolvents is limited to encapsulate hydrophobic drugs due to theintrinsic property of block copolymer. On the other hand, drugs loadedvia chemical bonding exhibit the shortcoming of insufficient loadingcapacity. In the present invention, the only requirement for the drug isto have a functional group that can donate a lone pair of electrons. Thechelating complex micelles are formed when drugs and polydentate ligandsbind to metal center at the same time. These micelles can carry not onlyhydrophobic but also hydrophilic drugs; thus, can be used extensively inthe drug delivery systems.

Furthermore, besides providing a linkage between polymer and drugmolecule, the following metal can be used for imaging analysis:gadolinium Gd(III) for MRI (magnetic resonance imaging), technetium^(99m)Tc for SPECT (single photon emission computed tomography), gallium⁶⁸Ga for PET/CT (positron emission tomography/computed tomography),rhenium ¹⁸⁸Re for internal radiation therapy, and indium ¹¹¹In for whiteblood cells magnetic resonance imaging. The application of thisinvention provides real-time monitoring techniques for imaging andtherapy. Incorporation of targeting moiety, such as folic acid, into CCMwill allow the accumulation of drugs in tumor tissues and accomplish theaim of selectively attacking cancer cells.

Another aim of the present invention is to provide a drug carrierloading with a cytoprotective agent. The carrier comprises a metal ion,which interacts with a cytoprotective agent (including amifostine,WR-1065) via coordinate bonds and at least one block copolymer(poly(ethylene glycol)-block-poly(glutamic acid); PEG-b-PGA) to form achelating complex micelle. The carboxylic acid on PGA and phosphonicacid on amifostine provide lone pairs of electrons, thus formingcoordinate bonds with metal. The PEG segments that without chelatingligands can extend outside the micelles, and therefore enhance theirdispersity.

Accordingly, the chelating complex micelles of the present inventioncontain polydentate ligands and metal ions can carry both hydrophobicand hydrophilic compounds. The advantages of biodegradability, excellentdispersity in aqueous solution, real-time monitoring, and longerhalf-live of drugs will fulfill a much needed developmental target inthe biomedical industry.

Based on the objectives stated in the preceding paragraphs, the presentinvention provides chelating complex micelles comprising a metal ioncore, which acts like a Lewis acid, and at least one ligand, whichinteracts with the metal ion through the coordinate bond. The metal inthe core is selected from the following list, including anycombinations, or combinations of its derivatives thereof: Fe, Cu, Ni,In, Ca, Co, Cr, Gd, Al, Sn, Zn, W, Sc, Ti, Mn, Mg, Be, La, Au, Ag, Cd,Hg, Pd, Re, Tc, Cs, Ra, Ir, Ga, and combinations thereof. The ligand isselected from the compound possessing functional groups in followinglist, including any combinations, or combinations of its derivativesthereof: carboxylic acids, alcohols, ketones, furans, amines, anilines,pyrroles, thiols, esters, amides, imines, pyridines, pyrimidines,imidazoles, pyrazols, sulfonamides, and phosphonic acids.

The chelating complex micelles also contain a drug molecule, which actas Lewis base. The drug molecule interacts with the metal in the corethrough coordinate bonding. The drug molecule contains one or morefunctional groups, which can be selected from the following listincluding any combinations or combinations of its derivatives thereof:carboxylic acid, alcohols, ketones, furans, amines, anilines, pyrroles,thiols, esters, amides, imines, pyridines, pyrimidines, imidazoles,pyrazols, sulfonamides, phosphonic acids. The drug can be selected fromthe following list, including any combinations or combinations of itsderivatives thereof: amifostine, WR-1065, doxorubicin, pemetrexed,gemcitabine, methotrexate, docetaxel, vinblastine, epirubicin,topotecan, irinotecan, ifosfamide, gefitinib, erlotinib, penicillinclass, cloxacillin, dicloxacillin, gentamicin, vancomycin, amphotericin,quinolones, piperazine, fluoroquinolone, nalidixic acid, ciprofloxacin,levofloxacin, trovafloxacin, oseltamivir, metformin, trastuzumab,imatinib, rituximab, bevacizumab, celecoxib, etodolac, ibuprofen,cyclosporine, morphine, erythropoietin, granulocyte colony-stimulatingfactor, curcumin (enol, keto form), glutathione, Vitamin C,acetylcysteine , carnitine, galantamine, insulin, imipenem, cilastatin,ertapenem, meropenem, entecavir, telbivudine, lamivudine, melatonin,tocopherols, tocotrienol (Vitamin E), L-carnitine, carotenes, ubiquinol,lipoic acid, polyphenols, catecholamine, resveratrol, piceid, tempo,asarone, aminoguanidine, tocopherol monoglucoside, glycyrrhizic acid,epicatechin, flavonoid, orientin, vicenin, MPG (2-mercaptopropionylglycine), and Mesna (2-mercaptoethanesulfonic acid).

Based on the objectives stated above, the present invention provides achelating complex micelle drug carrier, which contains at least onepolymer, at least one metal, and at least one drug molecule. The polymerand drug molecule, which act as Lewis base, link to metal Lewis acid viacoordinate bonding. The selection criteria of metal and drug moleculeare the same as the lists in preceding paragraphs. The polymers can beone of the following: unidentate ligands, bidentate ligands, tridentateligands, hexadentate ligands, and polydentate ligands. The molecularweight of the polymer is around 1,000-100,000 Dalton, and is selectedfrom the following list, including any combination or combination of itsderivatives thereof: poly(ethylene glycol), poly(aspartic acid),poly(glutamic acid), poly(acrylic acid), chitosan, polyethyleneimine,poly(methacrylic acid), hyaluronic acid, collagen, poly(N-isopropylacrylamide), amylose, cellulose, poly(hydroxybutyrate), poly(lacticacid), poly(butylenesuccinate), poly(caprolactone),carboxymethylcellulose, dextran, and cyclodextrin.

Based on the objectives stated above, the present invention provides apharmaceutical composition composed of chelating complex micelles, whichcontains at least one block copolymer, at least one drug molecule, andat least one metal. The block copolymer, which acts as a Lewis base,contains a chelating segment for coordinate bonding and a neutralsegment for better dispersion in biological fluids. The drug with afunctional group that can donate a lone pair of electrons is consideredas a Lewis base. Metal ions, which are invariably complexed withadditional ligands, are often sources of coordinatively unsaturatedderivatives that form Lewis adducts upon reaction with a Lewis base. Themetal ion mentioned above can be ferrous (Fe²⁺), ferric (Fe³⁺) orgadolinium (Gd³⁺); and the drug can be amifostine or WR-1065; and theblock copolymer is poly(ethylene glycol)-b-poly(glutamic acid)(PEG-b-PGA). The PGA is designed for chelating segment while PEG is theneutral segment used for enhancing dispersity in aqueous solution.

Based on the objectives stated above, the present invention provides amethod for preparing the pharmaceutical composition composed ofchelating complex micelles. The raw materials include amifostine,PEG-b-PGA block copolymer, and ferrous chloride FeCl₂ After well mixingin a buffer solution, amifostine, ferrous ion (Fe²⁺) and PEG-b-PGA blockcopolymer self-assembled to form the complex micelles via coordinatebonding. The amounts of the reactants used are: amifostine 0.1-10 mg,PEG-b-PGA 0.1-100 mg, and FeCl₂ 0.01-50 mg. The concentration ofamifostine is around 0.01-10 mg/mL, and the buffer can be HEPES[4-(2-hydroxyethyl)-1-piperazinee-thanesulfonic acid)], with a pH valueof 6.5 to 7.5. The temperature of the reaction is 4-40° C.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the schematic diagram of the production method for apharmaceutical composition composed of chelating complex micelles; it isbased on the third example of the present invention;

FIGS. 2A and 2B show the structures of amifostine and its derivativeWR-1065 of the present invention;

FIG. 3 shows the structure of block copolymer poly(ethyleneglycol)-b-poly(glutamic acid) of the present invention;

FIG. 4 shows the schematic diagram of chelating complex micelles loadedwith cytoprotective agent amifostine of the present invention;

FIG. 5 shows the GPC (gel permeation chromatography) analysis diagramfor PEG and PEG-b-PGA;

FIG. 6 shows the ¹H-NMR spectrum with corresponding chemical shift ofPEG-b-PGA;

FIG. 7 shows the size distribution of chelating complex micellesdetermined by DLS (dynamic light scattering);

FIG. 8 shows the in vitro released profiles of amifostine andamifostine-loaded CCM. The release ratio is decreased as increasing theamount of FeCl₂; and

FIG. 9 shows the in vitro released profiles of amifostine andamifostine-loaded CCM. The release ratio is decreased as increasing thereaction time.

DETAILED DESCRIPTION OF THE EMBODIMENTS

The present invention is directed to drug carriers. In order tofacilitate a thorough understanding of the present invention, detailedstructures, their elements and methods will be provided in the followingdescriptions. The implementations of the present invention are notlimited to specific details familiar to those engaged in and with fullknowledge of drug carrier. On the other hand, widely known structuresand their elements are omitted herein to avoid unnecessary limitationson the present invention. In addition, for better understanding andclarity of the description by those skilled in the art, components inthe figures are not necessarily drawn to scale; some scales may beexaggerated relative to others, and irrelevant parts are not completelypresented to provide a simpler and clearer figure. Preferred embodimentsof the present invention are described in details below. In addition,the present invention can be widely applicable to other embodiments, andthe scope of the present invention is not limited by such rather by thescope of the following claims.

According to the invention of the first embodiment, the presentinvention provides a drug carrier composed of chelating complexmicelles; the chelating complex micelles contain a metal ion core and atleast one ligand. The metal ion is a Lewis acid that interacts with theligands through coordinate bonds. The metal is selected from thefollowing lists, either as single one, its derivative, or anycombinations thereof: Fe, Cu, Ni, In, Ca, Co, Cr, Gd, Al, Sn, Zn, W, Sc,Ti, Mn, V, Mg, Be, La, Au, Ag, Cd, Hg, Pd, Re, Tc, Cs, Ra, Ir, and Ga.The ligand is selected from the following lists, either as single one,its derivatives or any combination thereof: carboxylic acids, alcohols,ketones, furans, amines, anilines, pyrroles, thiols, esters, amides,imines, pyridines, pyrimidines, imidazoles, pyrazols, sulfonamides, andphosphonic acids.

Chelating complex micelles use the metal ion as a core and conjugate thedrug molecule, which acts as a Lewis acid, via coordinate bonds. Thedrug Lewis base donates lone pairs of electrons in the coordinatebonding formation, and is selected from the following lists, either assingle one, its derivatives or any combination thereof: amifostine,WR-1065, doxorubicin, pemetrexed, gemcitabine, methotrexate, docetaxel,vinblastine, epirubicin, topotecan, irinotecan, ifosfamide, gefitinib,erlotinib, penicillin class, cloxacillin, dicloxacillin, gentamicin,vancomycin, amphotericin, quinolones, piperazine, fluoroquinolone,nalidixic acid, ciprofloxacin, levofloxacin, trovafloxacin, oseltamivir,metformin, trastuzumab, imatinib, rituximab, bevacizumab, celecoxib,etodolac, ibuprofen, cyclosporine, morphine, erythropoietin, granulocytecolony-stimulating factor, curcumin (enol, keto form), glutathione,Vitamin C, acetylcysteine, carnitine, galantamine, insulin, imipenem,cilastatin, ertapenem, meropenem, entecavir, telbivudine, lamivudine,melatonin, tocopherols, tocotrienol (Vitamin E), L-carnitine, carotenes,ubiquinol, lipoic acid, polyphenols, catecholamine, resveratrol, piceid,tempo, asarone, aminoguanidine, tocopherol monoglucoside, glycyrrhizicacid, epicatechin, flavonoid, orientin, vicenin, MPG(2-mercaptopropionyl glycine), and Mesna (2-mercaptoethanesulfonicacid).

According to the invention of the second embodiment, the inventionprovides a drug carrier composed of chelating complex micelles; thechelating complex micelles contain a metal ion core, at least onepolymer, and at least one drug molecule. The metal ion is considered asa Lewis acid while polymer chain and drug molecules are referred to asLewis bases. The Lewis bases (polymer chains and drug molecules) providelone pairs of electrons and conjugate to metal Lewis acid via coordinatebonding.

The polymer mentioned above can be monodentate (unidentate) ligands,bidentate ligands, the tridentate ligands, hexadentate ligands, andpolydentate ligands, with molecular weight in the range of 1,000-50,000Dalton. The polymer is selected from the following lists, either assingle one, its derivatives or any combinations thereof: poly(ethyleneglycol), polyaspartic acid, polyglutamic acid, polylysine. poly(acrylicacid), chitosan, polyethylenimine, poly(methacrylic acid), hyaluronicacid, collagen, poly(N-isopropyl acrylamide), amylose, cellulose,poly(hydroxybutyrate), poly(lactic acid), poly T(butylenesuccinate),poly(caprolactone), carboxymethyl cellulose, dextran, and cyclodextrin.

In addition, the selection criterion of drug Lewis base that donateslone pairs of electrons for the second embodiment is as same as thefirst embodiment. The selection criterion of metal Lewis acid is alsosimilarly described in the first embodiment.

According to the invention of the third embodiment, the inventionprovides a pharmaceutical composition composed of chelating complexmicelles for biomedical applications, such as cell protective agent. Thechelating complex micelles contain a metal ion core, at least one blockcopolymer and at least one drug molecule. The metal ion is considered asa Lewis acid while block copolymers and drug molecules are referred toas Lewis bases. The Lewis bases (block copolymers and drug molecules)provide lone pairs of electrons and conjugate to metal Lewis acid viacoordinate bonding.

The aforementioned metal ion includes an Fe (iron) or Gd (gadolinium)ion; the aforementioned drugs includes amifostine or WR-1065; and theaforementioned block copolymer possesses one chelating segment that canform coordinate bonds with metal ions, while the other end is theneutral segment used for enhancing dispersity in aqueous solution. Anexample of the block copolymer is poly(ethylene glycol)-b-poly(glutamicacid) (PEG-b-PGA). The PGA segment with excellent biocompatibilitypossesses carboxyl groups (—COO⁻) that can form coordinate bonds withmetal ions. On the other hand, the hydrophilic and neutralcharacteristics of the PEG segment makes the micelles well dispersed inbiological fluids. It is worth noting that PEG does not provide anyfunctional groups for coordinate bonding. Appropriate modification isnecessary to allow it to possess chelating ability. The PGA segment,which is a biodegradable polypeptide, is also used to link PEG and metalions.

The aforementioned drugs include amifostine or WR-1065. Amifostine hasfive functional groups that can donate lone pairs of electrons, i.e.,two —OH, one each of —P═O, NH and —NH₂; WR-1065 has three available, oneeach of —SH, —NH and —NH₂.

As illustrated in FIG. 1, the production of pharmaceutical composition(designated as 100) encompassing the chelating complex micelles is asfollows. Mix continuously 0.1-10 mg cytoprotective agent, amifostine(designated as 110), 0.1-100 mg PEG-b-PGA (designated as 120) and0.01-50 mg FeCl₂ (designated as 130) in 1-10 mL buffer solution at 4-40°C. for up to 48 hours. Based on the aforementioned bonding principle,amifostine (designated as 110), PEG-b-PGA (designated as 120), andferrous ion (Fe²) (designated as 130) self-assembled to form chelatingcomplex micelles with diameter around 10-300 nm. This chelating complexmicelle is designated as cytoprotective agent (designated as 300). Thebuffer solution can be 0.05 M HEPES(4-(2-hydroxyethyl)-1-piperazineethane-sulfonic acid) with a pH 6.5-7.5.

FIGS. 2A and 2B show the structures of amifostine and its derivativeWR-1065. FIG. 3 shows PEG-b-PGA. FIG. 4 shows the structure of chelatingcomplex micelles loaded with cytoprotective agent amifostine. In thisembodiment, PEG-b-PGA is synthesized using PEG as a macroinitiator. Theanalysis result of GPC (gel permeation chromatography) is shown in FIG.5. The M_(w) (weight-average molecular weight), M_(n) (number-averagemolecular weight), and PdI (polydispersity index) are 5700, 4900, and1.16, respectively. FIG. 6 shows the ¹H-NMR spectrum with correspondingchemical shift of PEG-b-PGA. FIG. 7 shows the size distribution ofchelating complex micelles determined by DLS (dynamic light scattering),which indicates that the Z-average diameter is 31.61 nm.

FIG. 8 shows the in vitro released profiles of amifostine andamifostine-loaded CCM. Five milligrams of amifostine, 20 mg of PEG-b-PGA(M_(w) 5700 Dalton), and 1.25-10 mg of FeCl₂ (weight ratio from 1:4:0.25to 1:4:2) are continuously mixing in 5 mL of buffer solution at 25° C.for 24 hours. The mixture is placed in a dialysis tube (with a molecularweight cut off 3500) and soaked in water to simulate the drug release.The results show that with 10 mg of FeCl₂ (weight ratio 1:4:2), most ofamifostine are trapped in the chelating complex micelles and cannotdiffuse through the dialysis membrane. The release ratio is decreased asincreasing the amount of FeCl₂. The above buffer solution is 0.05 MHEPES (4-(2-hydroxyethyl)-1-piperazineethane sulfonic acid), pH 7.0.

FIG. 9 shows the in vitro released profiles of amifostine andamifostine-loaded CCM. Five milligrams of amifostine, 20 mg of PEG-b-PGA(M_(w) 5700 Dalton), and 10 mg of FeCl₂ (weight ratio 1:4:2) arecontinuously mixing in 5 mL of buffer solution at 25° C. with variousreaction time. The mixture is placed in a dialysis tube (with amolecular weight cut off 3500) and soaked in water to simulate the drugrelease. The results show that after 24 hours of reaction, most ofamifostine are trapped in the chelating complex micelles and cannotdiffuse through the dialysis membrane. The release ratio is decreased asincreasing the reaction time. The above buffer solution is 0.05M ofHEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), pH 7.0.

In general, drug molecules are difficult to link to polymers in orderfor specific purposes. By the concept of coordinate bonding providedfrom the present invention, the metal Lewis acid, which can combine withdrugs and polymers to form chelating complex micelles at the same time.Such micelles not only possess the structure similar to the chelatingagent EDTA, but also prolong the half-life of drugs in the human body,and not causing human toxicity (EDTA will bind the metal elements in thebody). In addition, the coordinate bonding can also overcome the weakinteraction provided by ionic bonding. On the other hand, metal ions mayprecipitate under aqueous conditions as interacting with oxidants.Although PEG shows very good dispersion property in the aqueous solutionbut has no functional group to conjugate with other substances. Thus,PEG must be modified through introducing the PGA segment to chelatemetal ions, and prevent the precipitation of metal ions. It is worthnoting that the carrier of the present invention can be applied toeither hydrophilic or hydrophobic drugs, thus greatly enhancing itsapplication value. In addition, the FDA approved API (activepharmaceutical ingredient) may be regarded as a new drug if functionalgroups are changed. The safety and efficacy must be re-validated, thusdemanding extremely high capital investment. In contrast, the presentinvention is completely without any changes on the structure of drug andtherefore will not raise the problem of re-validation. Consequently, forthe processing compatibility, the present invention is exceptionallyvaluable.

It is apparent that based on the above descriptions of the embodiments,the present invention may have numerous modifications and alterations,and they should be construed within the scope of the following claims.In addition to the above detailed descriptions, the present inventioncan be widely applied to other embodiments. The above embodiments aremerely preferred embodiments of the present invention, and should not beused to limit the present invention in any way. Equivalent modificationsor changes made without departing from the principles of the presentinvention must be included in the following scope of the patent claims.

EXPLANATION OF THE SYMBOLS FOR THE MAJOR ELEMENTS

-   -   100 Pharmaceutical composition composed of chelating complex        micelles    -   110 cytoprotective agent amifostine    -   120 block copolymer poly(ethylene glycol)-b-poly(glutamic acid)        (PEG-b-PGA)    -   130 ferrous chloride (FeCl₂)

1. A chelating complex micelle, comprising: a metal ion core, whereinthe metal ion core is a Lewis acid; a ligand, wherein the ligand and themetal ion core bind to each other by coordinate bonds; and a drug,linking to the metal ion core via coordinate bonding, wherein the drugis a Lewis base.
 2. The chelating complex micelle of claim 1, whereinthe metal ion core is selected from the following lists: either singleone or any combination thereof, or derivatives thereof: Fe, Cu, Ni, In,Ca, Co, Cr, Gd, Al, Sn, Zn, W, Sc, Ti, Mn, V, Mg, Be, La, Au, Ag, Cd,Hg, Pd, Re, Tc, Cs, Ra, Ir, Ga.
 3. The chelating complex micelle ofclaim 1, wherein the ligand is selected from the following lists: eithersingle one or any combination thereof, or derivatives thereof:carboxylic acids, alcohols, ketones, furans, amines, anilines, pyrroles,thiols, esters, amides, imines, pyridines, pyrimidines, imidazoles,pyrazols, sulfonamides, phosphonic acid.
 4. The chelating complexmicelle of claim 1, wherein the drug contains one or more functionalgroups, which are selected from the following groups of carboxylic acid,alcohols, ketones, furans, amines, anilines, pyrroles, thiols, esters,amides, imines, pyridines, pyrimidines, imidazoles, pyrazols,sulfonamides, phosphonic acids, any combination thereof, and derivativesthereof.
 5. The chelating complex micelle of claim 1, the drug isselected from the following groups of amifostine, WR-1065, doxorubicin,pemetrexed, gemcitabine, methotrexate, docetaxel, vinblastine,epirubicin, topotecan, irinotecan, ifosfamide, gefitinib, erlotinib,penicillin class, cloxacillin, dicloxacillin, gentamicin, vancomycin,amphotericin, quinolones, piperazine, fluoroquinolone, nalidixic acid,ciprofloxacin, levofloxacin, trovafloxacin, oseltamivir, metformin,trastuzumab, imatinib, rituximab, bevacizumab, celecoxib, etodolac,ibuprofen, cyclosporine, morphine, erythropoietin, granulocytecolony-stimulating factor, curcumin (enol, keto form), glutathione,Vitamin C, acetylcysteine, carnitine, galantamine, insulin, imipenem,cilastatin, ertapenem, meropenem, entecavir, telbivudine, lamivudine,melatonin, tocopherols, tocotrienol (Vitamin E), L-carnitine, carotenes,ubiquinol, lipoic acid, polyphenols, catecholamine, resveratrol, piceid,tempo, asarone, aminoguanidine, tocopherol monoglucoside, glycyrrhizicacid, epicatechin, flavonoid, orientin, vicenin, MPG(2-mercaptopropionyl glycine), and Mesna (2-mercaptoethanesulfonicacid), any combination thereof, and any derivatives thereof.
 6. Achelating complex micelle for carrying a Lewis base drug, comprising: aLewis base polymer; and a metal ion core, wherein the metal ion core isa Lewis acid, and the metal ion core and the Lewis base polymers bind toeach other by coordinate bonds.
 7. The chelating complex micelle ofclaim 6, wherein the metal ion core is selected from a group of Fe, Cu,Ni, In, Ca, Co, Cr, Gd, Al, Sn, Zn, W, Sc, Ti, Mn, V, Mg, Be, La La, Au,Ag, Cd, Hg, Pd, Re, Tc, Cs, Ra, Ir, Ga, any combination thereof, and anyderivatives thereof.
 8. The chelating complex micelle of claim 6,wherein the Lewis base drug is selected from a group of amifostine,WR-1065, doxorubicin, pemetrexed, gemcitabine, methotrexate, docetaxel,vinblastine, epirubicin, topotecan, irinotecan, ifosfamide, gefitinib,erlotinib, penicillin class, cloxacillin, dicloxacillin, gentamicin,vancomycin, amphotericin, quinolones, piperazine, fluoroquinolone,nalidixic acid, ciprofloxacin, levofloxacin, trovafloxacin, oseltamivir,metformin, trastuzumab, imatinib, rituximab, bevacizumab, celecoxib,etodolac, ibuprofen, cyclosporine, morphine, erythropoietin, granulocytecolony-stimulating factor, curcumin (enol, keto form), glutathione,Vitamin C, acetylcysteine, carnitine, galantamine, insulin, imipenem,cilastatin, ertapenem, meropenem, entecavir, telbivudine, lamivudine,melatonin, tocopherols, tocotrienol (Vitamin E), L-carnitine, carotenes,ubiquinol, lipoic acid, polyphenols, catecholamine, resveratrol, piceid,tempo, asarone, aminoguanidine, tocopherol monoglucoside, glycyrrhizicacid, epicatechin, flavonoid, orientin, vicenin, MPG(2-mercaptopropionyl glycine), and Mesna (2-mercaptoethanesulfonicacid), any combination thereof, and any derivatives thereof.
 9. Thechelating complex micelle of claim 6, wherein the polymer is selectedfrom a group of unidentate ligand, bidentate ligands, tridentateligands, hexadentate ligands, and polydentate ligands.
 10. The chelatingcomplex micelle of claim 6, wherein the polymer's molecular weightranges from 1,000 to 100,000 Daltons.
 11. The chelating complex micelleof claim 6, wherein the polymer is selected from a group ofpoly(ethylene glycol), poly(aspartic acid), poly(glutamic acid),polylysine, poly(acrylic acid), chitosan, polyethyleneimine,poly(methacrylic acid), hyaluronic acid, collagen, poly(N-isopropylacrylamide), amylase, cellulose, poly(hydroxybutyrate), poly(lacticacid), poly(butylenesuccinate), poly(caprolactone),carboxymethylcellulose, dextran, cyclodextrin, any combination thereof,and any derivatives thereof.
 12. A pharmaceutical composition ofchelating complex micelles, comprising: a block copolymer, wherein thecopolymer is a Lewis base, and the copolymer comprises a chelatingsegment as a ligand, and a dispersing segment; a drug, which containsLewis base functional groups; and a metal ion core, wherein the metalion is a Lewis acid, and the metal ion core forms coordinate bonds withthe block copolymer and the drug.
 13. The pharmaceutical composition ofchelating complex micelles of claim 12, wherein the metal ion core isferrous ion, ferric ion, or a trivalent gadolinium ion.
 14. Thepharmaceutical composition of chelating complex micelles of claim 12,wherein the drug is an amifostine or WR-1065.
 15. The pharmaceuticalcomposition of chelating complex micelles of claim 12, wherein the blockcopolymer is poly(ethylene glycol)-b-poly(glutamic acid) (PEG-b-PGA),wherein poly(glutamic acid) (PGA) is the chelating segment, andpoly(ethylene glycol) (PEG) is the dispersing segment.
 16. A method ofmanufacturing a pharmaceutical composition having chelating type complexmicelles, consisting of: providing a raw material, the raw materialcontains an amifostine, a PEG-b-PGA and FeCl₂; and placing the rawmaterial in a buffer solution followed by continuous mixing, wherebyamifostine, via ferrous ion (Fe²), self-assembles with poly(ethyleneglycol)-b-poly(glutamic acid) (PEG-b-PGA) by coordinate bonding.
 17. Themethod of manufacturing a pharmaceutical composition having chelatingcomplex micelles of claim 16, wherein the amifostine weights between0.1-10 mg, the PEG-b-PGA weights between 0.1-100 mg, and the FeCl₂weights between 0.01 to 50 mg.
 18. The method of manufacturing apharmaceutical composition having chelating complex micelles of claim16, wherein the amifostine's concentration is about 0.01-10 mg/mL. 19.The method of manufacturing a pharmaceutical composition havingchelating complex micelles of claim 16, wherein the buffer solution isHEPES [4-(2-hydroxyethyl)-1-piperazinee-thanesulfonic acid)].
 20. Themethod of manufacturing a pharmaceutical composition having chelatingcomplex micelles of claim 16, wherein the buffer solution has a pH of6.5 to 7.5.
 21. The method of manufacturing a pharmaceutical compositionhaving chelating complex micelles of claim 16, wherein the mixingreaction is performed at a temperature between 4 to 40° C.